The shortcomings of clinical practice guidelines.

Accumulation of medical knowledge related to diagnosis and management over the last 5-6 decades has altered the course of diseases, improved clinical outcomes and increased survival. Thus, it has become difficult for the practicing physician to evaluate the long-term effects of a particular therapy on survival of an individual patient. Further, the approach by each physician to an individual patient with the same disease is not always uniform. In an attempt to assist physicians in applying newly acquired knowledge to patients, clinical practice guidelines were introduced by various scientific societies. Guidelines assist in facilitating the translation of new research discoveries into clinical practice; however, despite the improvements over the years, there are still several issues related to guidelines that often appear 'lost in translation'. Guidelines are based on the results of randomized clinical trials, other nonrandomized studies, and expert opinion (i.e. the opinion of most members of the guideline committees). The merits and limitations of randomized clinical trials, guideline committees, and presentation of guidelines will be discussed. In addition, proposals to improve guidelines will be presented.

Relationship of cardiac magnetic resonance imaging and myocardial biopsy in the evaluation of nonischemic cardiomyopathy.

This study was performed to determine the relative role of cardiac magnetic resonance (CMR) imaging and endomyocardial biopsy (EMB) in the evaluation of cardiomyopathy. Sixty-six patients with a clinical diagnosis of nonischemic dilated cardiomyopathy or restrictive cardiomyopathy underwent both EMB and CMR imaging as part of their diagnostic evaluation. The authors retrospectively reviewed the results of these two methods to determine their diagnostic impact and congruency. CMR imaging provided data on cardiac anatomy, left ventricular volumes, mass, and function in 85% of the patients, uncovered fibrosis in 31%, myocardial ischemia in 7%, and fibrofatty infiltration in two patients. EMB provided the histologic findings of cardiomyocyte hypertrophy in 77% of patients and substantial interstitial fibrosis in 59%. Six patients had EMB-proven amyloid heart disease, which was detected by CMR imaging in two. CMR imaging showed patterns of late gadolinium enhancement supportive of infiltrative disease or inflammation in 6 patients with EMB-proven definite (n=3) or borderline (n=3) myocarditis, but failed to do so in two other patients with borderline and two with resolving myocarditis. At the present time, CMR imaging and EMB remain complementary procedures in the evaluation of cardiomyopathic conditions.

Y-box binding protein-1 implicated in translational control of fetal myocardial gene expression after cardiac transplant.

Peri-transplant surgical trauma and ischemia/reperfusion injury in accepted murine heterotopic heart grafts has been associated with myofibroblast differentiation, cardiac fibrosis and biomechanical-stress activation of the fetal myocardial smooth muscle α-actin (SMαA) gene. The wound-healing agonists, transforming growth factor ß1 and thrombin, are known to coordinate SMαA mRNA transcription and translation in activated myofibroblasts by altering the subcellular localization and mRNA-binding affinity of the Y-box binding protein-1 (YB-1) cold-shock domain (CSD) protein that governs a variety of cellular responses to metabolic stress. YB-1 accumulated in polyribosome-enriched regions of the sarcoplasm proximal to cardiac intercalated discs in accepted heart grafts. YB-1 binding to a purine-rich motif in exon 3 of SMαA mRNA that regulates translational efficiency increased substantially in perfusion-isolated, rod-shaped adult rat cardiomyocytes during phenotypic de-differentiation in the presence of serum-derived growth factors. Cardiomyocyte de-differentiation was accompanied by the loss of a 60 kDa YB-1 variant that was highly expressed in both adult myocardium and freshly isolated myocytes and replacement with the 50 kDa form of YB-1 (p50) typically expressed in myofibroblasts that demonstrated sequence-specific interaction with SMαA mRNA. Accumulation of p50 YB-1 in reprogrammed, de-differentiated myocytes was associated with a 10-fold increase in SMαA protein expression. Endomyocardial biopsies collected from patients up to 14 years after heart transplant showed variable yet coordinately elevated expression of SMαA and p50 YB-1 protein and demonstrable p50 YB-1:SMαA mRNA interaction. The p60 YB-1 variant in human heart graft samples, but neither mouse p60 nor mouse or human p50, reacted with an antibody specific for the phosphoserine 102 modification in the YB-1 CSD. Modulation of YB-1 subcellular compartmentalization and mRNA-binding activity may be linked with reprogramming of contractile protein gene expression in ventricular cardiomyocytes that could contribute to maladaptive remodeling in accepted, long-term heart grafts.

Changes in plasma profiles of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in stress-induced cardiomyopathy.

BACKGROUND: Transient changes in the composition of the myocardial extracellular matrix may contribute to the ventricular systolic dysfunction in stress-induced cardiomyopathy (SIC). We examined the changes in plasma matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) that occur early after the clinical presentation of SIC. METHODS AND RESULTS: Ten patients with SIC were enrolled. Plasma concentrations of the 6 major MMPs (1, 2, 3, 7, 8, and 9) and all 4 TIMPs (1, 2, 3, and 4) were analyzed and compared with data from 15 control subjects. Within 24 hours of the clinical presentation, SIC patients had lower MMP-1 levels (0.41 ± 0.13 vs 0.70 ± 0.13 pg/mL; P = .048) and MMP-8 levels (1.61 ± 0.34 vs 4.84 ± 1.38 pg/mL; P = .001) and higher TIMP-4 levels (3.06 ± 0.40 vs 2.16 ± 0.18 pg/mL; P = .05) compared with control. Seven of 9 SIC patients had elevated LV end-diastolic pressures, and all had normal LV end-diastolic dimensions and volumes. CONCLUSIONS: Patients afflicted with SIC had MMP and TIMP profiles similar to those described in hypertensive heart disease and diastolic heart failure and different from the profiles following myocardial infarction. Our findings uncovered a unique biomolecular profile in SIC during the first 24 hours of presentation.

Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors.

BACKGROUND: Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. METHODS: The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel's expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs. RESULTS AND CONCLUSIONS: The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy.

Role of the pulmonary artery catheter in diagnosis and management of heart failure.

The pulmonary artery catheter will likely earn a place in the history of medicine as one of the most useful tools that shaped our understanding and management of various diseases. An intense assessment of its application in nonacute and nonshock decompensated heart failure has been provided by the ESCAPE trial, a landmark investigation that showed an overall neutral impact of pulmonary artery catheter-guided therapy over therapy guided by clinical evaluation and judgment alone. The current guidelines reserve the use of a pulmonary artery catheter for the management of refractory heart failure and select conditions. The pulmonary artery catheter remains a useful instrument in clinical situations when clinical and laboratory assessment alone is insufficient in establishing the diagnosis and pathophysiologic condition, and in guiding effective, safe therapy.

Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors.

Hypertension is a mechanism-based toxic effect of drugs that inhibit the vascular endothelial growth factor signaling pathway (VSP). Substantial evidence exists for managing hypertension as a chronic condition, but there are few prospectively collected data on managing acute hypertension caused by VSP inhibitors. The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to evaluate this problem, to make recommendations to the Cancer Therapy Evaluation Program on further study, and to structure an approach for safe management by treating physicians. The panel reviewed: the published literature on blood pressure (BP), hypertension, and specific VSP inhibitors; abstracts from major meetings; shared experience with the development of VSP inhibitors; and established principles of hypertension care. The panel generated a consensus report including the recommendations on clinical concerns summarized here. To support the greatest possible number of patients to receive VSP inhibitors safely and effectively, the panel had four recommendations: 1) conduct and document a formal risk assessment for potential cardiovascular complications, 2) recognize that preexisting hypertension will be common in cancer patients and should be identified and addressed before initiation of VSP inhibitor therapy, 3) actively monitor BP throughout treatment with more frequent assessments during the first cycle of treatment, and 4) manage BP with a goal of less than 140/90 mmHg for most patients (and to lower, prespecified goals in patients with specific preexisting cardiovascular risk factors). Proper agent selection, dosing, and scheduling of follow-up should enable maintaining VSP inhibition while avoiding the complications associated with excessive or prolonged elevation in BP.

Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score.

OBJECTIVES: Identifying high-risk heart failure (HF) patients at hospital discharge may allow more effective triage to management strategies. BACKGROUND: Heart failure severity at presentation predicts outcomes, but the prognostic importance of clinical status changes due to interventions is less well described. METHODS: Predictive models using variables obtained during hospitalization were created using data from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial and internally validated by the bootstrapping method. Model coefficients were converted to an additive risk score. Additionally, data from FIRST (Flolan International Randomized Survival Trial) was used to externally validate this model. RESULTS: Patients discharged with complete data (n = 423) had 6-month mortality and death and rehospitalization rates of 18.7% and 64%, respectively. Discharge risk factors for mortality included BNP, per doubling (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.15 to 1.75), cardiopulmonary resuscitation or mechanical ventilation during hospitalization (HR: 2.54, 95% CI: 1.12 to 5.78), blood urea nitrogen, per 20-U increase (HR: 1.22, 95% CI: 0.96 to 1.55), serum sodium, per unit increase (HR: 0.93, 95% CI: 0.87 to 0.99), age >70 years (HR: 1.05, 95% CI: 0.51 to 2.17), daily loop diuretic, furosemide equivalents >240 mg (HR: 1.49, 95% CI: 0.68 to 3.26), lack of beta-blocker (HR: 1.28, 95% CI: 0.68 to 2.41), and 6-min walk, per 100-foot increase (HR: 0.955, 95% CI: 0.99 to 1.00; c-index 0.76). A simplified discharge score discriminated mortality risk from 5% (score = 0) to 94% (score = 8). Bootstrap validation demonstrated good internal validation of the model (c-index 0.78, 95% CI: 0.68 to 0.83). CONCLUSIONS: The ESCAPE study discharge risk model and score refine risk assessment after in-hospital therapy for advanced decompensated systolic HF, allowing clinicians to focus surveillance and triage for early life-saving interventions in this high-risk population. (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE]; NCT00000619).

Are hemodynamic parameters predictors of mortality?

This article addresses a question that the authors consider to be somewhat rhetorical: are hemodynamic parameters predictors of mortality? It reviews the specific hemodynamic abnormalities and pathophysiologic consequences distinctive to the patient who has decompensation and addresses the data that implicate abnormal hemodynamics as a treatment target associated with increased mortality. The focus is on patients who have decompensated heart failure, defined as left ventricular systolic dysfunction and an acute, subacute, or gradual worsening of symptoms while receiving optimal medical therapy.

Role of the pulmonary artery catheter in diagnosis and management of heart failure.

The pulmonary artery catheter will likely earn a place in the history of medicine as one of the most useful tools that shaped our understanding and management of various diseases. An intense assessment of its application in nonacute and nonshock decompensated heart failure has been provided by the ESCAPE trial, a landmark investigation that showed an overall neutral impact of pulmonary artery catheter-guided therapy over therapy guided by clinical evaluation and judgment alone. The current guidelines reserve the use of a pulmonary artery catheter for the management of refractory heart failure and select conditions. The pulmonary artery catheter remains a useful instrument in clinical situations when clinical and laboratory assessment alone is insufficient in establishing the diagnosis and pathophysiologic condition, and in guiding effective, safe therapy.

Predictors of inpatient outcomes in hospitalized patients after left heart catheterization.

Clinical and laboratory factors predicting inpatient outcomes, specifically in-hospital mortality and length of stay (LOS), have not been defined for hospitalized patients specifically referred for left heart catheterization and coronary angiography (LHC). The objective of the study was to determine these outcomes and their predictors in hospitalized patients after LHC. Multivariate logistic regression models were used to identify risk factors for in-hospital mortality and Cox proportional hazards models were used to identify factors determining LOS in 9,420 consecutive patients hospitalized for LHC. Odds ratio for in-hospital mortality and hazard ratio for prolonged LOS were derived. The strongest predictors of mortality were advanced age, left ventricular (LV) end-diastolic pressure (EDP), LV ejection fraction (EF), systemic blood pressure, and renal insufficiency. Predictors of prolonged LOS were LVEDP, LVEF, 3-vessel coronary artery disease, and valvular disease. Clinical and laboratory characteristics of patients with an LVEF > or =50% were also compared with those of patients with an LVEF <50%. Predictors of mortality and LOS remained the same for patients with an LVEF <50%. For an LVEF > or =50%, LVEDP also determined LOS and chronic renal insufficiency provided predictive power to mortality and LOS in this subgroup. In conclusion, several readily attainable clinical and laboratory parameters predict inpatient mortality and LOS in hospitalized patients referred for LHC.

Latent development of occlusive coronary atherosclerosis as a cause of decompensation of non-ischemic dilated cardiomyopathy.

Four patients with chronically well-compensated, non-ischemic dilated cardiomyopathy (NIDC) presented with occlusive atherosclerotic coronary artery disease as the cause of subacute decompensation (FC III-IV heart failure) 8-13 years following the diagnosis of NIDC. In addition to the atherogenic condition of heart failure, 3 of the patients acquired major atherosclerotic risk factors (dyslipidemia, diabetes mellitus) during the interval between the diagnoses of NIDC and problematic atherosclerotic coronary disease. For each patient, dyspnea on exertion was the primary symptom during the subacute decompensation. Only 1 patient noted precordial chest pain in the form of atypical angina during some of the dyspneic events. The diagnosis of occlusive coronary artery disease was made by coronary angiography, followed by angioplasty-stent deployment in 3 patients and coronary artery bypass surgery in 1; all improved to their baseline FC I-II status following these coronary interventions. As survival of patients with NIDC increases, occlusive coronary artery disease may enter an otherwise stable clinical course to provoke unanticipated decompensation (principally dyspnea), and can do so without causing angina pectoris as a heralding symptom.

Changing preferences for survival after hospitalization with advanced heart failure.

OBJECTIVES: This study was designed to analyze how patient preferences for survival versus quality-of-life change after hospitalization with advanced heart failure (HF). BACKGROUND: Although patient-centered care is a priority, little is known about preferences to trade length of life for quality among hospitalized patients with advanced HF, and it is not known how those preferences change after hospitalization. METHODS: The time trade-off utility, symptom scores, and 6-min walk distance were measured in 287 patients in the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheter Effectiveness) trial at hospitalization and again during 6 months after therapy to relieve congestion. RESULTS: Willingness to trade was bimodal. At baseline, the median trade for better quality was 3 months' survival time, with a modest relation to symptom severity. Preference for survival time was stable for most patients, but increase after discharge occurred in 98 of 145 (68%) patients initially willing to trade survival time, and was more common with symptom improvement and after therapy guided by pulmonary artery catheters (p = 0.034). Adjusting days alive after hospital discharge for patients' survival preference reduced overall days by 24%, with the largest reduction among patients dying early after discharge (p = 0.0015). CONCLUSIONS: Preferences remain in favor of survival for many patients despite advanced HF symptoms, but increase further after hospitalization. The bimodal distribution and the stability of patient preference limit utility as a trial end point, but support its relevance in design of care for an individual patient.

High mortality without ESCAPE: the registry of heart failure patients receiving pulmonary artery catheters without randomization.

BACKGROUND: In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), there was no difference in days alive and out of the hospital for patients with decompensated heart failure randomly assigned to therapy guided by pulmonary artery catheter (PAC) plus clinical assessment versus clinical assessment alone. The external validity of these findings is debated. METHODS AND RESULTS: ESCAPE sites enrolled 439 patients receiving PAC without randomization in a prospective registry. Baseline characteristics, pertinent trial exclusion criteria, reasons for PAC use, hemodynamics, and complications were collected. Survival was determined from the National Death Index and the Alberta Registry. On average, registry patients had lower blood pressure, worse renal function, less neurohormonal antagonist therapy, and higher use of intravenous inotropes compared with trial patients. Although clinical assessment anticipated less volume overload and greater hypoperfusion among the registry population, measured filling pressures were similarly elevated in the registry and trial patients, whereas measured perfusion was slightly higher among registry patients. Registry patients had longer hospitalization (13 vs 6 days, P < .001) and higher 6-month mortality (34% vs 20%, P < .001) than trial patients. CONCLUSIONS: The decision to use PAC without randomization identified a population with higher disease severity and risk of mortality. This prospective registry highlights the complex context of patient selection for randomized trials.

Serum response factor neutralizes Pur alpha- and Pur beta-mediated repression of the fetal vascular smooth muscle alpha-actin gene in stressed adult cardiomyocytes.

Mouse hearts subjected to repeated transplant surgery and ischemia-reperfusion injury develop substantial interstitial and perivascular fibrosis that was spatially associated with dysfunctional activation of fetal smooth muscle alpha-actin (SM alpha A) gene expression in graft ventricular cardiomyocytes. Compared with cardiac fibroblasts in which nuclear levels of the Sp1 and Smad 2/3 transcriptional-activating proteins increased markedly after transplant injury, the most abundant SM alpha A gene-activating protein in cardiomyocyte nuclei was serum response factor (SRF). Additionally, cardiac intercalated discs in heart grafts contained substantial deposits of Pur alpha, an mRNA-binding protein and known negative modulator of SRF-activated SM alpha A gene transcription. Activation of fetal SM alpha A gene expression in perfusion-isolated adult cardiomyocytes was linked to elevated binding of a novel protein complex consisting of SRF and Pur alpha to a purine-rich DNA element in the SM alpha A promoter called SPUR, previously shown to be required for induction of SM alpha A gene transcription in injury-activated myofibroblasts. Increased SRF binding to SPUR DNA plus one of two nearby CArG box consensus elements was observed in SM alpha A-positive cardiomyocytes in parallel with enhanced Pur alpha:SPUR protein:protein interaction. The data suggest that de novo activation of the normally silent SM alpha A gene in reprogrammed adult cardiomyocytes is linked to elevated interaction of SRF with fetal-specific CArG and injury-activated SPUR elements in the SM alpha A promoter as well as the appearance of novel Pur alpha protein complexes in both the nuclear and cytosolic compartments of these cells.